Structural basis of odorant recognition by a mammalian class II odorant receptor

Mammalian odorant receptors (ORs) sense diverse environmental chemicals, yet structural insights into odorant recognition by mammalian class II ORs remain limited. Here, we present the cryo-EM structure of a native mammalian class II OR, mouse Olfr412, a human OR1D2 ortholog, bound to the odorant methyl-<i>trans</i>-cinnamate and the G_s protein. The odorant-binding pocket of Olfr412 is located deeper within the transmembrane domain than that of the class I OR OR51E2 and is largely composed of poorly conserved hydrophobic residues, providing a structural basis for broad odorant recognition in class II ORs. Structural and molecular dynamics analyses suggest that the conserved Y^6x55 plays a key role in odorant recognition and activation, functionally paralleling R^6x59 in class I ORs and is further stabilized by intramolecular interaction with the conserved ECL2 residue E^45x51. Together, our findings uncover structural mechanisms underlying odorant recognition and activation in class II ORs.